The Effect of Mandated Bone Protective Agents on Fracture Risk With Longer Follow-Up (EORTC 1333 / PEACE III Trial) – Fred Saad
June 8, 2021
Bone strengthening agents such as bisphosphonates or the RANKL-targeting antibody denosumab reduced the bone loss associated with androgen deprivation therapy (ADT) and prevent skeletal-related events in castration resistant prostate cancer (CRPC). The use of these agents is recommended in CRPC by many guidelines. The randomized phase III EORTC-1333-GUCG also known as the PEACE-III trial, compares enzalutamide versus a combination of Radium 223 and enzalutamide in asymptomatic or mildly symptomatic metastatic castration-resistant prostate cancer (mCRPC) patients. At the 2021 ASCO annual meeting, an updated analysis of fracture incidence with longer follow-up of the phase III PEACE-III trial was presented. In this conversation with Charles Ryan, Fred Saad highlights this data presented confirming the early fracture rate results.
Fred Saad, MD, FRCS, Professor and Chief of Urology, Director of GU Oncology, Raymond Garneau Chair in Prostate Cancer, University of Montreal Hospital Centre (CHUM), Director, Prostate Cancer Research, Institut du cancer de Montréal/CRCHUM
Charles J. Ryan, MD. the B.J. Kennedy Chair in Clinical Medical Oncology at the University of Minnesota and Director of the Division of Hematology, Oncology and Transplantation.
Charles Ryan: Hello from ASCO 2021. Chuck Ryan here from the University of Minnesota, and I'm talking today with Fred Saad who is the Head of Urology and the Medical Director of the Interdisciplinary Urology Oncology Group at the University Hospital of Montreal, where he's also the Director of Prostate Cancer Research and Professor of Surgery. Fred, great to see you.
Fred Saad: It's great to see you too, even though it's only virtual, eh, Chuck?
Charles Ryan: Right. Well, it beats nothing, I guess. And you have got a couple of abstracts to talk about today. One of which is, this is almost a follow-up conversation to a conversation you and I had at, I believe it was ESMO a couple of years ago, more than a couple of years ago now, around the interaction of AR targeted therapies and bone protective agents, and at that time we had a conversation about the ERA 223 study and the high rate of fractures that led to the discontinuation of that study, and here you are part of a team reporting the PEACE III trial, which combines radium-223 with enzalutamide. And the study went through a little bit of a switch where patients were, based on ERA 223, mandated to have bone protective agents. And you are reporting, really, the effect of that switch. Tell us highlights of this data.
Fred Saad: Yeah, so the background, very briefly, about the study is to see if we can improve on the standard of care, which is an AR targeted therapy that I think most people would agree has become the standard for first-line mCRPC treatment, and to see if introducing radium before and during treatment with AR targeted therapy, rather than waiting for them to fail docetaxel, would make sense. So the study really is looking not only at fractures and skeletal-related events, but actually progression-free survival. So the design is enzalutamide alone versus enzalutamide and radium-223. And we both discussed ERA 223 that had abiraterone and prednisone in combination with radium, and I think many of us thought this was a little bit unique. The abiraterone, the prednisone might be leading to these increases in fractures. So I think many of us, including myself thought maybe this doesn't occur with enzalutamide, which doesn't have prednisone, doesn't reduce testosterone further.
So the study looked at the patients who came in early on, and early on there was no mandate for a bone protective agent, and about almost 50% were on one, but that means that over 50% were not on a bone protective agent. And the data was reported at ASCO a couple of years ago on the fracture rate, and this is standing up now, patients who came in without a bone protective agent had a very high fracture rate, especially when you combine it with radium-223, and patients with radium and enzalutamide had about a 40%, 45% fracture rate in those patients. But what's surprising is in the group of enzalutamide alone, it was a 21% fracture rate. So it's been a long-term using ADT and following patients that you realize just to what degree fractures are going to occur. And then when the... yes, sorry.
Charles Ryan: No, no, that's a great background, and I think the speculation back then was that the effectiveness of the therapy mandated that with response to the treatment, the bones would heal and that perhaps the radium was impairing the healing of those bones. And so the takeaway message, perhaps, at that time was that there was an interaction between the two, and the data certainly supported that.
Fred Saad: Right, absolutely. And once ERA reported, this is what woke up PEACE III, the study that we are talking about, to mandate bone protective agents.
Charles Ryan: Yeah.
Fred Saad: And once they mandated it, it plummeted, the fracture rate plummeted in both arms, not only the radium, but the radium and the enzalutamide arm went down to below 3%.
Charles Ryan: Right, right.
Fred Saad: Compared to a very, very worrisome fracture rate when you do not use a bone protective agent in patients with mCRPC.
Charles Ryan: So I think the takeaway message would be that bone protective agents should be utilized at any time we are using a combination, or do you think bone protective agents should be considered standard of care now whenever we're using radium?
Fred Saad: For radium, I think definitely, because I think radium in itself, because of the inhibition of the osteoblast, actually prevents the bone from healing, and you actually need the osteoclastic inhibition to counteract the benefits that you get from radium, but also the detriments of inhibiting bone reformation. But I think it's across the board, and there were a lot of discussions. Do we really need it while patients are still responding, exactly like you said, while on abi or enza, or do we wait for them to fail?
Charles Ryan: Right.
Fred Saad: And so even just looking at the enzalutamide arm alone, we went down from 21% fracture rate to less than 3%. I mean, that in itself, I think, is something that we need to consider in patients that we're keeping alive longer and longer. So the point about fractures may be impacting overall survival is something that we had looked at years ago, and in prostate and breast cancer, fractures in themselves were an independent predictor of worse survival. So I think we really have to focus beyond PSA, beyond imaging, but really think about the lives of these patients by supporting their bones adequately.
Charles Ryan: In the ERA 223 study there was an association in an adverse survival in patients in the combination arm, presumably due to the fact that fractures led to some disability and probably decreased therapy down the road, or even in certain cases fractures can lead to death, complications from fractures can lead to death. And so it's possible that correcting this problem is going to enhance the potential benefit of this therapy. When, and what do you think this means, if anything, for the overall outcomes of PEACE III?
Fred Saad: Well, I think that remains to be seen, I mean, whether the combination early or delaying the introduction of radium is going to help, not only in terms of SRE but actually in terms of progression-free survival, is going to be awaited. So the trial is still ongoing, it's recruiting very well now that we've mandated and we've gotten rid of this, I guess, dark cloud around ERA 223 that actually stunted the recruitment, and now it's really gone up in these patients. So I'm very much looking forward to the efficacy outcomes, but at least for the safety outcomes, this is, I think, the real deal.
Charles Ryan: Yeah, no, I agree. And of course, I was baiting you a little bit, but I think that what we saw in ERA 223, the safety was probably a huge driver of the negative survival outcome, and in this case, correcting that may allow us to have a real sense of what this combination of therapies could do. So this is great data, and understandably important to be presented even before we have the primary outcomes of the study, because of the safety angle, and congratulations to you and the team, and Dr. Gillessen for presenting this, and to you also for being a champion of bone protective therapy for a long time now in men with metastatic prostate cancer to bone.
Fred Saad from Montreal, thanks for joining us.